The anti-tumor effect and the toxicity of any regimen are obviously related to the concentrations of the active components of the drugs to which tumor and normal tissues are exposed. It has been shown that pharmacokinetic-based individual dose modulation of busulfan can reduce the incidence of veno-occlusive disease and ensure adequate therapeutic drug exposure for allogeneic cell engraftment. We also know that other chemotherapy agents and auxiliary drugs such as antiemetics will interfere with the metabolism and pharmacokinetics of the agents used in the high-dose cyclophosphamide, cisplatin, BCNU (CPB) regimen. Therefore, the first Specific Aim of this project is to evaluate and implement methods to conduct pharmacokinetic-based dose individualization of CPB. We are pursuing this by a three tiered strategy of: dose individualization based on the pharmacokinetics of CPB in an individual patient; use of relatively innocuous metabolic probes to predict CPB exposure; and pre-screening patients? DNA for polymorphisms in genes which are thought to control the metabolism of CPB. The latter effort is being conducted through collaboration with our project on the Duke breast cancer SPORE grant. The goal of this work will be to reduce inter-patient variability and thus variance in outcome/toxicity. In addition, such a platform will provide us with a more consistent patient group to test innovative strategies directed at reversal of drug resistance, as outlined below. The extent and duration of cytoreduction produced by any regimen is undoubtedly related to the drug sensitivity of the patient?s tumor. Data suggest that some patients would benefit from inhibition of resistance-related enzymes such as O 6 -methyl transferase, while others may benefit from (and tolerate) additional dose escalation. Aim 2 intends to conduct clinical trials to explore both of these strategies with a goal of improving the efficacy of high-dose chemotherapy without worsening its therapeutic index. The characteristics of patients being enrolled into the mini-allogeneic transplant studies described in Project 2 would suggest that pharmacokinetic variability might be even wider in this population. Aim 3 of this project proposes to conduct a detailed pharmacokinetic/pharmacodynamic evaluation of the cyclophosphamide/fludarabine combination used in this regimen. The focus will be evaluation of factors that may explain and predict inter-patient variability in addition to investigation of relationships between systemic drug exposure and immunosuppression/engraftment.